DCAF13 promotes breast cancer cell proliferation by ubiquitin inhibiting PERP expression.
DCAF13 promotes breast cancer cell proliferation by ubiquitin inhibiting PERP expression.
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DCAF13通过泛素抑制PERP表达促进乳腺癌细胞增殖
作者：
进化保守的DDB1‐和CUL4‐相关因子13 （DCAF13）是最近发现的cullin环指泛素连接酶4 (CRL4) E3泛素连接酶的底物受体，调节细胞周期进程。DCAF13在许多癌症中过度表达，尽管其在乳腺癌中的作用目前尚不清楚。在本研究中，我们发现DCAF13在人乳腺癌中过表达，且其过表达与预后不良密切相关，提示DCAF13可能作为诊断标志物和治疗靶点。我们利用CRISPR/Cas9敲除乳腺癌细胞系中的DCAF13，发现DCAF13的缺失在体外和体内均显著降低了乳腺癌细胞的增殖、克隆形成和迁移。此外，DCAF13缺失促进乳腺癌细胞凋亡和衰老，并诱导细胞周期阻滞在G1/S期。全基因组RNAseq分析和western blotting显示，DCAF13的缺失导致p53凋亡效应因子PMP22 （PERP）的mRNA和蛋白积累。敲低PERP可部分逆转DCAF13敲低诱导的细胞增殖障碍。Co -免疫沉淀实验显示DCAF13和DNA损伤结合蛋白1 （DDB1）直接与PERP相互作用。过表达DDB1显著增加PERP多泛素化，提示CRL4DCAF13 E3连接酶靶向PERP泛素化和蛋白酶体降解。综上所述，DCAF13及其下游效应物PERP在乳腺癌增殖中起关键作用，并可能作为预后和治疗靶点。DCAF13在乳腺癌中过表达，其过表达与预后不良密切相关。DCAF13缺失显著降低了乳腺癌细胞的增殖、克隆形成和迁移。DCAF13通过抑制PERP的表达促进乳腺癌细胞增殖。
Evolutionarily conserved DDB1‐and CUL4‐associated factor 13 (DCAF13) is a recently discovered substrate receptor for the cullin RING‐finger ubiquitin ligase 4 (CRL4) E3 ubiquitin ligase that regulates cell cycle progression. DCAF13 is overexpressed in many cancers, although its role in breast cancer is currently elusive. In this study we demonstrate that DCAF13 is overexpressed in human breast cancer and that its overexpression closely correlates with poor prognosis, suggesting that DCAF13 may serve as a diagnostic marker and therapeutic target. We knocked down DCAF13 in breast cancer cell lines using CRISPR/Cas9 and found that DCAF13 deletion markedly reduced breast cancer cell proliferation, clone formation, and migration both in vitro and in vivo. In addition, DCAF13 deletion promoted breast cancer cell apoptosis and senescence, and induced cell cycle arrest in the G1/S phase. Genome‐wide RNAseq analysis and western blotting revealed that loss of DCAF13 resulted in both mRNA and protein accumulation of p53 apoptosis effector related to PMP22 (PERP). Knockdown of PERP partially reversed the hampered cell proliferation induced by DCAF13 knockdown. Co‐immunoprecipitation assays revealed that DCAF13 and DNA damage‐binding protein 1 (DDB1) directly interact with PERP. Overexpression of DDB1 significantly increased PERP polyubiquitination, suggesting that CRL4DCAF13 E3 ligase targets PERP for ubiquitination and proteasomal degradation. In conclusion, DCAF13 and the downstream effector PERP occupy key roles in breast cancer proliferation and potentially serve as prognostics and therapeutic targets. DCAF13 is overexpressed in breast cancer and its overexpression closely correlates with the poor prognosis. DCAF13 deletion markedly decreased breast cancer cell proliferation, clone formation, and migration both in vitro and in vivo.DCAF13 promotes breast cancer cell proliferation by inhibiting the expression of PERP.
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